Osteoporosis is an enormous public health problem in the United States, affecting an estimated 26 million European-American women who experience over a million osteoporosis-related fractures each year at a cost exceeding $10 billion. Our specific aims attempt to fill gaps in knowledge that impede the design and implementation of an effective control program for this disorder. AIM 1) By extending follow-up on our original age- stratified sample of Rochester, MN women for up to 20 years, we will assess the long-term predictability of fractures from baseline measurement of potential risk factors, including bone mineral density (BMD) of the spine and hip. This will permit validation, from prospective data, of theoretical models of long-term fracture risk which are being proposed to aid in clinical decision making. AIM 2) On newly developed cohorts of Rochester women and men, and on an additional sample of minority residents of Rochester, we will make comprehensive studies to define gender-specific differences in age-related BMD and bone turnover (cross-sectionally) and bone loss (longitudinally) and to establish the effects that residual levels of serum sex and adrenal steroids, age-related increases in serum parathyroid hormone, and fat mass and serum insulin have on modulating these changes. We will also determine if risk for osteoporosis is modified by differences in vitamin D receptor (VDR) genotypes and whether these can predict BMD and rates of bone loss. By evaluating these complex relationships simultaneously in population-based, parallel studies of men and women, we hope to resolve conflicting data and refine hypotheses of osteoporosis pathophysiology. AIM 3) By drawing a new random sample of rural Olmsted County men and women for comparison with Rochester residents, we will determine whether the effects of physical activity on BMD are mediated by lean body mass and whether differences in activity and muscle mass account for higher BMD in rural residents and, thus, the lower incidence of hip fractures that has been observed in rural Olmsted County compared with Rochester. AIM 4) Finally, after reassessing diagnostic criteria with follow-up roentgenograms, we will use quantitative radiographic vertebral morphometry to estimate the prevalence of vertebral fractures in Rochester men compared to women. Additional comparisons with women from Charleston, SC will help determine whether there are differences in prevalence due to race- or gender-specific differences in BMD or vitamin D metabolism. In all of these studies, we will continue to rely heavily on the Rochester Epidemiology Project, a unique resource for population-based epidemiologic studies. We will employ state-of-the-art methods using dual energy x-ray absorptiometry to assess total and regional BMD and lean body mass, new biochemical markers for bone turnover, and molecular biology techniques for assessing genetic predisposition to osteoporosis. This research will allow us to identify and quantify the determinants of bone loss and fractures in the general population so as to recognize better those individuals at risk for osteoporosis, who could then be targeted for preventive intervention.